Interaction between interleukin-1β and type-1 cannabinoid receptor is involved in anxiety-like behavior in experimental autoimmune encephalomyelitis.

Antonietta Gentile,Diego Centonze,Helena Sepman,Georgia Mandolesi,Alessandra Musella,Alessandro Usiello,Silvia Bullitta,Francesca De Vito,Beat Lutz,Roberta Fantozzi,Nicola B Mercuri,Mauro Maccarrone,Diego Fresegna

doi:10.1186/s12974-016-0682-8

Abstract

BackgroundMood disorders, including anxiety and depression, are frequently diagnosed in multiple sclerosis (MS) patients, even independently of the disabling symptoms associated with the disease. Anatomical, biochemical, and pharmacological evidence indicates that type-1 cannabinoid receptor (CB1R) is implicated in the control of emotional behavior and is modulated during inflammatory neurodegenerative diseases such as MS and experimental autoimmune encephalomyelitis (EAE).MethodsWe investigated whether CB1R could exert a role in anxiety-like behavior in mice with EAE. We performed behavioral, pharmacological, and electrophysiological experiments to explore the link between central inflammation, mood, and CB1R function in EAE.ResultsWe observed that EAE-induced anxiety was associated with the downregulation of CB1R-mediated control of striatal GABA synaptic transmission and was exacerbated in mice lacking CB1R (CB1R-KO mice). Central blockade of interleukin-1β (IL-1β) reversed the anxiety-like phenotype of EAE mice, an effect associated with the concomitant rescue of dopamine (DA)-regulated spontaneous behavior, and DA-CB1R neurotransmission, leading to the rescue of striatal CB1R sensitivity.ConclusionsOverall, results of the present investigation indicate that synaptic dysfunction linked to CB1R is involved in EAE-related anxiety and motivation-based behavior and contribute to clarify the complex neurobiological mechanisms underlying mood disorders associated to MS.

Highlights

Mood disorders, including anxiety and depression, are frequently diagnosed in multiple sclerosis (MS) patients, even independently of the disabling symptoms associated with the disease
EAE-induced anxiety is associated with Type-1 cannabinoid receptor (CB1R) desensitization in the striatum We investigated the anxiety-like phenotype associated with MOG-induced central inflammation in presymptomatic EAE mice
Significant differences between EAE and controls emerged at the light/dark test (LDT) (Fig. 1a–a”), since the time spent in the light zone (EAE 16.42 ± 4.6 %; Complete Freund’s adjuvant (CFA): 42.21 ± 4.72 %; unpaired T test; p < 0.01; Fig. 1a) and the number of rearing episodes during LDT (CFA: 23 ± 3.32, n = 8; EAE: 11.38 ± 2.33, n = 8, unpaired T test: p < 0.05; Fig. 1a’) were reduced in EAE, indicating both anxietylike behavior and reduced motivation-based activity, respectively, in accordance with our previous findings [8]

Summary

Introduction

Mood disorders, including anxiety and depression, are frequently diagnosed in multiple sclerosis (MS) patients, even independently of the disabling symptoms associated with the disease. Anatomical, biochemical, and pharmacological evidence indicates that type-1 cannabinoid receptor (CB1R) is implicated in the control of emotional behavior and is modulated during inflammatory neurodegenerative diseases such as MS and experimental autoimmune encephalomyelitis (EAE). Studies in the experimental autoimmune encephalomyelitis (EAE), the most characterized murine model of MS, have clearly highlighted the independence of behavioral alterations from motor disability and, most notably, the involvement of cytokines [7,8,9,10]. Endocannabinoid signaling enhancement has antidepressant and anxiolytic actions in humans [25] and in rodents [26, 27], and genetic or pharmacological blockade of CB1R promotes depression- and anxiety-like behavior in humans [28, 29] and in rodents [30,31,32]

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Conclusion